Composition and method for treatment of diabetes

ABSTRACT

The present invention relates to a method of treating an incretin related disease such as diabetes, obesity and the like by delivery of butyric acid, bile acid, long chain fatty acid or glutamine to the colon by bypassing the upper digestive tract. The composition is combined either by the same or different route of administration with a monoamine reuptake inhibitor such as buproprion.

The application claims priority of U.S. Provisional application61/245,036 filed on Sep. 23, 2009 and is included herein in its entiretyby reference.

COPYRIGHT NOTICE

A portion of the disclosure of this patent contains material that issubject to copyright protection. The copyright owner has no objection tothe reproduction by anyone of the patent document or the patentdisclosure as it appears in the Patent and Trademark Office patent filesor records, but otherwise reserves all copyright rights whatsoever.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel method and composition methodfor treating diabetes, metabolic syndrome, hypertriglyceridemia andobesity. In particular, the present invention relates to the treatmentof diabetes, metabolic syndrome, hypertriglyceridemia and obesity bydelivering specific, naturally occurring compounds in combination withmonoamine reuptake inhibitors to the lower gut in a manner that preventsincreased addictive behaviors during treatment.

2. Description of Related Art

The use of bariatric surgery is a popular and very effective method oftreating obesity. It has been reported though that those persons loosingweight after such surgery frequently exhibit other addictive typebehaviors to replace the eating addictive cycle. Addictive behaviorssuch as alcohol, drugs, gambling, sex addition and the like arereported. In addition, increased hunger cravings in some people havebeen reported. It has been theorized that the bariatric surgery, whilecorrecting the physiological problem with food intake, does not dealwith the hedonic reward system which contributes to increased eatingobserved in obesity. Therefore, while the surgery corrects peripheralproblems it creates a discrepancy between amounts of food consumed andthe need to be compensated in a psychological reward stimulation system.

Diabetes mellitus is a worldwide health threat of increasing magnitudeand is considered a major health risk both in developed and indeveloping countries. Type II diabetes accounts for the vast majority ofthe cases involving diabetes and accounts suggest it is the seventhleading cause of death in the United States. It appears that the majorcontributing factor to the incidence of Type II diabetes is beingoverweight. In the United States alone, it is estimated that over 17.6million individuals suffer from diabetes and it is estimated that anadditional 5.7 million individuals are unaware they have diabetes. Inaddition, there are about 57 million Americans who are consideredpre-diabetic.

Type II diabetes is also known as non-insulin dependent diabetesmellitus. It generally manifests itself as an inability to adequatelyregulate blood-glucose levels. This is as opposed to Type I diabeteswhich is characterized by defects in pancreatic production of insulin.In other words, it appears that Type II diabetic individuals suffer frominsulin resistance. The factors that have been identified incontributing to the development of Type II diabetes include one or moreof obesity, genetic background, age, diet and lack of exercise. Type IIis frequently called “adult onset” but because diet is a factor it canarise at virtually any age.

The Type II diabetes can cause glucose levels to rise in the blood andurine which in turn can cause hunger, urination, thirst and metabolismrelated issues. If the condition is not treated, the most common seriousresults include heart disease, kidney disease and blindness. Severaltreatments are currently used. Because obesity is frequently a causalagent in diabetes, diet and exercise are usually a front line defense.Therapeutic agents are also used as a second line of defense includinguse of insulin or pharmaceuticals that reduce blood and urine levels ofglucose.

Several drugs are in current use for Type II diabetes including insulinsecretagogues, glucose lowering effectors, GLP-1 analogs, DPPIVinhibitors, activators of the peroxisome proliferator activatedreceptor-gamma and alpha-glucosidase inhibitors. Because these currenttreatments have several problems associated with them, there is still aneed for alternative therapies to treat Type II diabetes.

Gut hormones are a type of gastrointestinal hormone that, among others,cause an increase in the amount of insulin released from the beta cellsof the islets of Langerhans after eating, even before blood glucoselevels become elevated. They are secreted in their highest level fromL-cells in the colon. They also slow the rate of absorption of nutrientsinto the blood stream by reducing gastric emptying and may directlyreduce food intake. They also inhibit glucagon release from the alphacells of the Islets of Langerhans. Glucagon like peptide-1 (GLP-1),which is frequently called an incretin, is a gut hormone secreted by Lcells. Glucagon like peptide-1 (GLP-1) (an incretin) has been identifiedas one composition that if its secretion is stimulated can possibly beused to treat diabetes.

GLP-1 is a peptide secreted from enteroendocrine L cells and has a widevariety of physiological effects that have been described in numerouspublications over the past two decades. More recently, much research hasbeen focused on the use of GLP-1 in the treatment of conditions anddisorders such as diabetes mellitus, stress, obesity, appetite controland satiety, Alzheimer's, inflammation, and diseases of the centralnervous system. However, the use of a peptide in clinical treatment isseverely limited due to difficult administration, and lack of sufficientin vivo stability. Therefore, a small molecule that either mimicked theeffects of GLP-1 directly, or increased GLP-1 secretion, has beenthought to be the treatment of choice in increasing incretin productionin the treatment of the variety of conditions or disorders describedabove, namely diabetes mellitus and obesity.

PYY is a gut hormone (Peptide YY) which is a short (36 amino acid)protein released by cells in the ileum and colon in response to foodintake. In humans it reduces appetite. PYY is found in L-cells in themucosa of the gastrointestinal tract especially in the ileum and colon.There is also a small amount of PYY, about 1-10 percent, in theesophagus, the stomach, the duodenum and jejunum. PYY concentration inthe circulation increases postprandially (after food ingestion) anddecreases by fasting.

GLP-2 (a gut hormone) is a 33 amino acid peptide, co-secreted along withGLP-1 from intestinal endocrine cells in the small and large intestine.GLP-2 among others stimulates mucosal growth in the small and largeintestine, inhibits gastric emptying and gastric acid secretion, reducesintestinal permeability, and stimulates intestinal blood flow.

Oxyntomodulin (a gut hormone) is a 37 amino acid peptide co-secretedalong with GLP-1 from L-cells that mimics the effects of GLP-1 and GLP-2on gastric acid secretion and gut motility, suppresses appetite andreduces food intake in normal humans and reduces energy intake by ˜17%,in overweight and obese human subjects with no effect on water intake.

Butyric acid is a naturally occurring fatty acid occurring in the formof esters in animal fats and plant oils. For example, the triglycerideof butyric acid makes up 3% to 4% of butter. It is found in rancid foodssuch as rancid butter and rancid cheese and has a very unpleasant smelland taste. It is an important member of the fatty acid sub-group calledthe short chain fatty acids.

Bile acids (also known as bile salts) are steroid acids foundpredominantly in the bile of mammals. In humans, taurocholic acid andglycocholic acid (derivatives of cholic acid) represent approximatelyeighty percent of all bile acids. The two major bile acids are cholicacid, and chenodeoxycholic acid. They, their conjugates, and their7-alpha-dehydroxylated derivatives are all found in human intestinalbile. An increase in bile flow is exhibited with an increased secretionof bile acids. Bile acid's main function is to facilitate the formationof micelles, which promotes dietary fat processing. Bile saltsconstitute a large family of molecules, composed of a steroid structurewith four rings, a five or eight carbon side-chain terminating in acarboxylic acid, and the presence and orientation of different numbersof hydroxyl groups. The four rings are labeled from left to right (ascommonly drawn) A, B, C, and D, with the D-ring being smaller by onecarbon than the other three. The hydroxyl groups have a choice of beingin 2 positions, either up (or out), termed beta (often drawn byconvention as a solid line), or down, termed alpha (shown as a dashedline in drawings). All bile acids have a hydroxyl group on position 3,which was derived from the parent molecule, cholesterol. In cholesterol,the 4 steroid rings are flat and the position of the 3-hydroxyl is beta.

Long chain fatty acids (LCFA) are fatty acids with aliphatic tails of 16carbons or more. Fatty acids are aliphatic monocarboxylic acids, derivedfrom, or contained in esterified form in an animal or vegetable fat, oilor wax. Natural fatty acids commonly have a chain of 4 to 28 carbons(usually unbranched and even numbered), which may be saturated orunsaturated.

Glutamine is an amino acid that is used as a nutritional supplement inthe treatment of a variety of diseases, including cancer. Glutamine isthe most abundant free amino acid in the human body and, in addition toits role as a component of protein, serves a variety of functions in thebody. It is a non-essential amino acid because it is made by body cells.In addition, most dietary proteins contain ample amounts of glutamineand healthy people usually obtain all the additional glutamine that theyneed in their diet.

The above naturally occurring products are difficult to administerespecially because taste of these products is extremely unpalatable andthey are easily degraded in the digestive tract and/or absorbed.

Obesity is a medical condition that is reaching epidemic proportionsamong humans in a number of countries throughout the world. It is acondition that is also associated with, or induces, other diseases orconditions that disrupt life's activities and lifestyles. Obesity isrecognized as a serious risk factor for other diseases and conditionssuch as diabetes, hypertension, and arteriosclerosis and can contributeto elevated levels of cholesterol in the blood. It is also recognizedthat increased body weight due to obesity can place a burden on joints,such as knee joints, causing arthritis, pain, and stiffness. Obesity cancontribute to certain skin conditions such as atopic dermatitis and bedsores. Because overeating and obesity have become such a problem in thegeneral population, many individuals are now interested in losingweight, reducing weight, and/or maintaining a healthy body weight andlifestyle.

Hypertriglyceridemia (hTG) is a common disorder in the United States.The condition is exacerbated by uncontrolled diabetes mellitus, obesity,and sedentary habits, all of which are more prevalent in industrializedsocieties, particularly the United States, than in developing nations.In both epidemiologic and interventional studies, hypertriglyceridemiais a risk factor for coronary artery disease (CAD). Treatment ofhypertriglyceridemia is by restriction of carbohydrates and fats in thediet, as well as with niacin, fibrates and statins (three classes ofdrugs). Increased fish oil intake may substantially lower anindividual's triglycerides.

There are obviously a number of compositions designed to deliver amedicament to the lower gut. Such compositions include thethree-component matrix structures such as disclosed in U.S. Pat. No.7,431,943 to Villa et al. issued Oct. 7, 2008 and incorporated herein inits entirety by reference.

A number of new approaches to stimulation of the receptors which appearto stimulate gut hormones such as the GPR 120, TGR5, GPR 41 and GPR 43receptors are being tried. In patent applications: WO/2008/067219published Jun. 5, 2008; US2007/060759 published Nov. 8, 2007;JP2006-6304A published Mar. 9, 2006 and JP 2006-56881 A published Mar.2, 2006 there are disclosed several classes of small molecules agoniststhat have been designed to stimulate the TGR5 receptor, a bile acidG-protein-coupled receptor.

A number of different formulations are available for delivery of desiredcompositions to the colon including amylose coated tablets, entericallycoated chitosan tablets, matrix within matrix or multimatrix systems orpoly-saccaride coated tablets. One example of multimatrix controlledrelease systems are disclosed in U.S. Pat. No. 7,431,943 issued Oct. 72008 to Villa et al and incorporated herein by reference. Disclosed is amatrix within matrix design wherein a lipophilic phase and amphiphilicphase are incorporated within the inner matrix and at least a portion ofthe active ingredient is incorporated into the amphiphilic phase.

Monoamine reuptake inhibitors fall into a number of classes includingserotonin, norepinephrine and dopamine reuptake inhibitors. They arefrequently used as antidepressants and some of them have been used totreat one or more addictive behaviors. Bupropion is a monoamine reuptakeinhibitor. It is both a norepinephrine and dopamine reuptake inhibitor.It is known to be used in smoking cessation, and in some cases fortreatment of obesity and attention deficit hyperactivity disorder. Manymonoamine reuptake inhibitors are dual or even triple reuptakeinhibitors having all three activities in a single composition.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to the discovery that certain naturallyoccurring compositions can be delivered to the colon or rectally so asto bypass the stomach and upper digestive system and increase theproduction of certain gut hormones from L cells. This can be used totreat a wide variety of gut hormone deficiency related conditionsincluding obesity and diabetes. In order to treat the loss of thestimulation of a reward system that may occur with treatment of someindividuals in this treatment, the method of treating diabetes orobesity will be combined with a composition that blocks or inhibitsmonoamine reuptake. In addition, the combination therapy is better attreating obesity and related diseases than either of the compositionsadministered alone.

In one embodiment of the present invention, there is a method oftreating or preventing a condition or disorder affected by the decreasedor lack of release of a gut hormone secreted from L cells by stimulatingthe production of an L cell secreted gut hormone in the colon of anindividual comprising:

-   -   a) selecting an agent causing gut hormones secretion from        L-cells from the group comprising butyric acid, a bile acid, a        long chain fatty acid and glutamine, the composition formulated        to release in a colon targeted delivery system or in a rectal        release system;    -   b) administering sufficient stimulating pharmaceutical        composition to the individual via a colon targeted delivery        system sufficient to cause a release of gut hormones from the        L-cell in the colon of the individual sufficient to achieve the        desired result; and    -   c) administering a sufficient amount of a monoamine reuptake        inhibitor to the individual sufficient to ameliorate an increase        in compulsive behavior caused by step b).

In yet another embodiment of the present invention, there is disclosed apharmaceutical composition for inducing the release of a gut hormonefrom an L-cell;

-   -   a) a composition selected from the group comprising butyric        acid, a bile acid, a long chain fatty acid and glutamine        formulated such that it does not release in either the stomach        or upper gastro intestinal tract; and    -   b) a monoamine reuptake inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

This detailed description defines the meaning of the terms used hereinand specifically describes embodiments in order for those skilled in theart to practice the invention.

The terms “a” or “an”, as used herein, are defined as one or as morethan one. The term “plurality”, as used herein, is defined as two or asmore than two. The term “another”, as used herein, is defined as atleast a second or more. The terms “including” and/or “having”, as usedherein, are defined as comprising (i.e., open language). The term“coupled”, as used herein, is defined as connected, although notnecessarily directly, and not necessarily mechanically.

Reference throughout this document to “one embodiment”, “certainembodiments”, and “an embodiment” or similar terms means that aparticular feature, structure, or characteristic described in connectionwith the embodiment is included in at least one embodiment of thepresent invention. Thus, the appearances of such phrases or in variousplaces throughout this specification are not necessarily all referringto the same embodiment. Furthermore, the particular features,structures, or characteristics may be combined in any suitable manner inone or more embodiments without limitation.

The term “or” as used herein is to be interpreted as an inclusive ormeaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

Term “means” preceding a present participle of an operation indicates adesired function for which there is one or more embodiments, i.e., oneor more methods, devices, or apparatuses for achieving the desiredfunction and that one skilled in the art could select from these ortheir equivalent in view of the disclosure herein and use of the term“means” is not intended to be limiting.

As used herein, the term “treating” refers to alleviating the specifiedcondition, eliminating or reducing the symptoms of the condition,slowing or eliminating the progression of the condition and preventingor delaying the initial occurrence of the condition in a subject, orreoccurrence of the condition in a previously afflicted subject.

As used herein a “condition” or “disorder” refers to any disease state,a particular state of a mammal or the like to which an increase in theproduction of a gut hormone from L cells would affect in a positive ornegative way. Included are the disease states noted herein but ingeneral this refers to any state so affected by increasing gut hormonesin a desired manner. The gut hormone system is known in mammals and, assuch, the present invention relates to the treatment of a mammal. In oneembodiment the mammal is a human. Conditions for treatment by increasinga gut hormone from L cells production include, but are not limited to,Type I diabetes, Type II diabetes, obesity, appetite control, metabolicsyndrome, and polycystic ovary syndrome.

The gut hormone secretion in the present invention is stimulated inL-cells present in the colon, normally in response to the presence ofnutrients in the gut. While such cells are present in other parts of thedigestive tract and other parts of the organism, they have the highestconcentration in the colon. Stimulation of L-cells in the colon resultsin the most effective production of gut hormones possible and thus, themost effective treatment. Gut hormones from L-cells of the presentinvention include but are not limited to GLP-1, GP-2, PYY andoxyntomodulin. Incretins such as GLP-1, in particular, are a gut hormoneof interest in one embodiment.

The compounds of the invention for stimulating gut hormone release arenatural compounds selected from the group comprising butyric acid, abile acid, a long chain fatty acid and glutamine. It is understood thatthis includes combinations of the compounds as well as each compoundindividually.

As used herein the term “monoamine reuptake inhibitors” (MRI's) as usedherein refers to compositions which are either: serotonin,norepinephrine or dopamine reuptake inhibitors. These compositions areknown to be effective in treating compulsive disorders. MRI's can bedual or even triple inhibitors and be in all three subclasses of MRI's.In one embodiment, the MRI is bupropion a norepinephrine, dopaminereuptake inhibitor (a dual inhibitor).

As used herein, “a compound” of the present invention includes allcompounds described herein.

The compounds of the present invention may crystallize in more than oneform, a characteristic known as polymorphism, and such polymorphic forms(“polymorphs”) are within the scope of the present invention.Polymorphism generally can occur as a response to changes intemperature, pressure, or both. Polymorphism can also result fromvariations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility, and melting point.

Certain compounds described herein contain one or more chiral centers,or may otherwise be capable of existing as multiple stereoisomers. Thescope of the present invention includes mixtures of stereoisomers aswell as purified enantiomers or enantiomerically/diastereomericallyenriched mixtures. Also included within the scope of the invention arethe individual isomers of the compounds of the present invention, aswell as any wholly or partially equilibrated mixtures, thereof. Thepresent invention also includes the individual isomers of the compoundsrepresented by the formulas above as mixtures with isomers, thereof, inwhich one or more chiral centers are inverted.

Typically, but not absolutely, the compounds herein include the salts ofthe present compositions and include the pharmaceutically acceptablesalts. Salts encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention.Salts of the compounds of the present invention may include acidaddition salts. Representative salts include acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, calcium edetate,camsylate, carbonate, clavulanate, citrate, dihydrochloride, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, monopotassium maleate, mucate, napsylate, nitrate,N-methylglucamine, oxalate, pamoate (embonate), palmitate, pantothenate,phosphate/diphosphate, polygalacturonate, potassium, salicylate, sodium,stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate,tosylate, thethiodide, thmethylammonium, and valerate salts. Othersalts, which are not pharmaceutically acceptable, may be useful in thepreparation of compounds of this invention and these should beconsidered to form a further aspect of the invention.

“Administering” of the gut hormone from L-cells stimulating compositionas used herein refers to the oral or rectal administration of anincretin stimulating composition of the present invention. As describedelsewhere herein, the compounds are so formulated to be taken orally anddelivered to the colon bypassing the upper digestive tract and stomachor rectally to deliver the composition to the colon.

The “administering” of a composition of the present invention can referto oral, rectal, IV, IM or the like and is not dependant on anyparticular means of administration. The MRI can be administered alongwith the gut hormone stimulating composition, or sequentially. The MRI'scan be administered by the same or different route than the incretinstimulating composition. The amount of the MRI administered by thepresent invention is an amount which ameliorates the additional transferthat can occur from the administration of the incretin stimulatingcomposition of the present invention. Gut hormone stimulatingcompositions of the invention need to bypass the upper GI while theMRI's do not, thus, leading to the possibility of a bifurcatedadministration regimen. One skilled in the art would be able todetermine the exact amount which depends on the particular MRI as wellas the individual involved in therapy with the present invention. Sincesome of the MRI's, e.g. bupropion, also have an anti-obesity effect, itis anticipated that combinations of these types of MRI's with the guthormone stimulating compositions will have a much greater or synergisticeffect when compared to the treatment with these compositions alone. Inthe treatment with bupropion the average dose, in one embodiment, wouldbe from about 0.1 mg/kg to about 10 mg/kg.

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal, or human that is being sought, forinstance, by a researcher or clinician.

The term “therapeutically effective amount” means any amount which, ascompared to a corresponding subject who has not received such an amount,results in improved treatment, healing, prevention, amelioration of adisease, disorder, side effect, or a decrease in the rate of advancementof a disease or disorder. The term also includes within its scopeamounts effective to enhance normal physiological function. Atherapeutically effective amount will produce a “therapeutic effect”.

For use in therapy, therapeutically effective amounts of a compound ofthe present invention, as well as salts thereof, are presented as apharmaceutical composition formulated to release in a colon targeteddelivery system.

The present invention provides pharmaceutical compositions that includeeffective amounts of a compound as herein described, or a salt thereof,and one or more pharmaceutically acceptable carriers, diluents, orexcipients. The carrier(s), diluent(s) or excipient(s) must beacceptable, in the sense of being compatible with the other ingredientsof the formulation and not deleterious to the recipient of thepharmaceutical composition and consistent with the mode ofadministration i.e. oral or rectal.

In accordance with another aspect of the invention there is alsoprovided a process for the preparation of a pharmaceutical formulation,including admixing a compound of the present invention or salts thereof,with one or more pharmaceutically acceptable carriers, diluents orexcipients.

A therapeutically effective amount of a compound of the presentinvention will depend upon a number of factors. For example, thespecies, age, and weight of the recipient, the precise conditionrequiring treatment and its severity, the nature of the formulation, andthe type of colon targeted delivery system are all factors to beconsidered. The therapeutically effective amount ultimately should be atthe discretion of the attendant, physician or veterinarian. Regardless,an effective amount of an incretin stimulating compound of the presentinvention for the treatment of humans suffering from diabetes or anoverweight condition and associated conditions, generally, should be inthe range of 0.01 to 100 mg/kg body weight of recipient (mammal) perday. More usually the effective amount should be in the range of 0.3 to30 mg/kg body weight per day. Thus, for a 70 kg adult mammal the actualamount per day would usually be from 21 to 2100 mg. This amount may begiven in a single dose per day or in a number (such as two, three, four,five, or more) of sub-doses per day such that the total daily dose isthe same. An effective amount of a salt or solvate thereof, may bedetermined as a proportion of the effective amount of the compound ofthe present invention per se. Similar dosages should be appropriate fortreatment of the other conditions referred to herein.

Pharmaceutical formulations may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of anincretin stimulating compound of the present invention, depending on thecondition being treated, the route of administration, and the age,weight, and condition of the patient. Preferred unit dosage formulationsare those containing a daily dose or sub-dose, as herein above recited,or an appropriate fraction thereof, of an active ingredient. Suchpharmaceutical formulations may be prepared by any of the methods wellknown in the pharmacy art.

The compounds of the present invention, or a salt thereof, areadministered by a targeted drug delivery system. In one embodiment, thedelivery systems may be employed for targeting drug delivery to thecolon and bypassing the upper digestive system and stomach. Such drugdelivery systems include covalent linkage compositions, polymer coatedcompositions, compositions embedded in matrices, time releasedcompositions, redox-sensitive polymer compositions, bioadhesivecompositions, micropartical coating compositions, and osmotic deliverycompositions. Suitable compositions include those containingpolysaccharides, such as chitosan, pectin, chondroitin sulphate,cyclodexthn, dextrans, guar gum, inulin, amylose and locust bean gum.The compounds may also be coupled with soluble polymers. Such polymerscan include polyvinylpyrrolidone (PVP), pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethyl-aspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds may becoupled to a class of biodegradable polymers; for example, polylacticacid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, andcross-linked or amphipathic block copolymers of hydrogels. Those ofparticular effectiveness in the present invention include embodiments ofmultimatrix targeted systems. Of particular effectiveness in the presentinvention are the targeted matrix in matrix systems comprising aformulation of a hydrophilic first matrix, comprising a lipophlic phaseand an amphiphilic phase, wherein the liphphilic phase and theamphiphilic phase are in a second matrix together and the second matrixis dispersed throughout the hydrophilic first matrix and wherein thepharmaceutical composition containing the compound is at least partiallyincorporated into the amphiphilic phase. Examples of some of the matrixin matrix formulations are disclosed in U.S. Pat. No. 7,431,943 as notedabove. Those skilled in the art will appreciate the use of suchcompositions for the purposes of targeting delivery of the compounds ofthe present invention, or a salt thereof, to the colon of the subjectbeing treated. The methods for the formulation of such compositions fortargeted delivery are within the skill in the art, in view of thisdisclosure.

The compounds of the present invention, or a salt thereof, may beemployed alone or in combination with other therapeutic agents. Thecompound(s) of the present invention and the other pharmaceuticallyactive agent(s) may be administered together or separately and, whenadministered separately, administration may occur simultaneously orsequentially, in any order. The amounts of the compound(s) of thepresent invention and the other pharmaceutically active agent(s) and therelative timings of administration will be selected in order to achievethe desired combined therapeutic effect. The administration incombination of a compound of the present invention or a salt, or solvatethereof, with other treatment agents may be in combination byadministration concomitantly in: (1) a unitary pharmaceuticalcomposition including both compounds; or (2) separate pharmaceuticalcompositions each including one of the compounds. Alternatively, thecombination may be administered separately in a sequential mannerwherein one treatment agent is administered first and the other secondor vice versa. Such sequential administration may be close in time orremote in time.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g. containing conventionalsuppository bases such as cocoa butter or other glycerides. Thecompositions so formulated will be designed to give an effective dosageto the colon in addition to other areas a rectal administration mightaffect.

The compounds of the present invention may be used in the treatment of avariety of disorders and conditions. As such, the compounds of thepresent invention may be used in combination with a variety of othertherapeutic agents useful in the treatment of those disorders orconditions. As discussed briefly above, current diabetes therapiesinclude diet, exercise, insulin, insulin secretagogues, glucose-loweringeffectors, PPAR-γ agonists, and α-glucosidase inhibitors. The compoundsof the present invention may be combined with these or other medicaltherapies to treat and/or prevent diabetes and associated disorders andconditions, including but not limited to, diabetes Types I and II,obesity, glucose intolerance, insulin resistance, metabolic syndrome,hyperlipidemia, hypercholesterolemia, artheroscelrosis,neurodegenerative diseases, and other indications such as inflammationand stroke. For example, in the treatment of Type II diabetes, acompound of the present invention may be combined with one or morepharmaceutically active agents, including metformin, sulfonylureas suchas glyburide and glipizide, repaglinide, nateglinide, thiazolidinedionessuch as rosiglitazone and pioglitazone, acarbose, miglitol, exanatide,pramlintide, and insulin.

EXAMPLES Example 1

Drug is delivered as an enema or suppositories made as described in¹(containing 1 g of glutamine). 10 overnight fasted obese diabeticpatients with impaired gut hormone effect³ and/or impaired gut hormonesecretion^(4,5) are dosed rectally with one suppository (or enema). 30minutes after drug administration, patients are subjected to OralGlucose Tolerance Test (OGTT) or standardized meal. Blood is collectedat the following time points: −30, 0, 5; 10, 15, 30, 60, 90, and 120minutes. Blood is analyzed for levels of: glucose, insulin, GLP-1, PYY,other hormones and lipids. Glucose and lipids (after standardized meal)levels are measured after treatment regime and shown to decrease.

Example 2

Drug is delivered as an enema or suppositories made as described in¹(containing 2 g of butyric acid). 10 overnight fasted obese diabeticpatients with impaired incretin effect³ and/or impaired gut hormonesecretion^(4,5) are dosed rectally with one suppository (or enema). 30minutes after drug administration, patients are subjected to OralGlucose Tolerance Test (OGTT) or standardized meal. Blood is collectedat the following time points: −30, 0, 5; 10, 15, 30, 60, 90, and 120minutes. Blood is analyzed for levels of: glucose, insulin, GLP-1, PYY,other hormones and lipids. Glucose and lipids' (after standardized meal)levels are measured after treatment regime and their levels are shown todecrease.

Example 3

Tablets formulated with MMX technology (containing 1 g of glutamine) aremade as described in². 10 overnight fasted obese diabetic patients withimpaired gut hormone effect³ and/or impaired gut hormone secretion^(4,5)are dosed with one MMX tablet at 8:00 AM. 4 hrs after drugadministration, patients are subjected to Oral Glucose Tolerance Test(OGTT) or standardized meal. Blood is collected at the following timepoints: −30, 0, 5; 10, 15, 30, 60, 90, and 120 minutes. Blood isanalyzed for levels of: glucose, insulin, GLP-1, PYY, other hormones andlipids. Glucose and lipids' (after standardized meal) levels aremeasured after treatment regime and their levels are shown to decrease.

Example 4

Tablets formulated with MMX technology (containing 2 g of butyric acid)are made as described in². 10 overnight fasted obese diabetic patientswith impaired gut hormone effect³ and/or impaired gut hormonesecretion^(4,5) are dosed with one MMX tablet at 8:00 AM. 4 hrs afterdrug administration, patients are subjected to Oral Glucose ToleranceTest (OGTT) or standardized meal. Blood is collected at the followingtime points: −30, 0, 5; 10, 15, 30, 60, 90, and 120 minutes. Blood isanalyzed for levels of: glucose, insulin, GLP-1, PYY, other hormones andlipids. Glucose and lipids' (after standardized meal) levels aremeasured after treatment regime and their levels are shown to decrease.

Example 5

Tablets formulated with MMX technology (containing 1 g of glutamine) aremade as described in². 10 obese diabetic patients with impaired incretineffect³ and/or impaired incretin secretion^(4,5) are dosed with one MMXtablet at 8:00 AM before first meal for six (6) weeks. HbA1c, fastingglucose and insulin are measured before treatment and at 1, 2, and 6weeks after initiation of the treatment. Additionally, patients aresubjected at these times to Oral Glucose Tolerance Test (OGTT) orstandardized meal. Blood is collected at the following time points: −30,0, 5; 10, 15, 30, 60, 90, and 120 minutes. Blood is analyzed for levelsof: glucose, insulin, GLP-1, PYY, other hormones and lipids. Glucoselevels are measured to decrease after treatment regime. The treatmentalso caused triglycerides levels to be lower than pre-treatment levels.

Example 6

Tablets formulated with MMX technology (containing 2 g of butyric acid)are made as described in². 10 obese diabetic patients with impaired guthormone effect³ and/or impaired gut hormone secretion^(4,5) are dosedwith one MMX tablet at 8:00 AM before first meal for six (6) weeks.HbA1c, fasting glucose and insulin are measured before the treatment andat 1, 2, and 6 weeks after initiation of the treatment. Additionally,patients are subjected at these times to Oral Glucose Tolerance Test(OGTT) or standardized meal. Blood is collected at the following timepoints: −30, 0, 5; 10, 15, 30, 60, 90, and 120 min. Blood is analyzedfor levels of: glucose, insulin, GLP-1, PYY, other hormones and lipids.Glucose levels are measured to decrease after treatment regime. Thetreatment also caused triglycerides levels to be lower thanpre-treatment levels.

Example 7

Each of the above examples are combined with oral administration ofbupropion (Wellbutrin XL, Zyban) 300 mg timed released tablet oncedaily. Patients are observed for the appearance of secondary compulsivedisorders after the administration of the combination therapy. It isobserved that the combination therapy results in an improved score inhunger/satiety survey conducted post dosing or reduced food intakemeasured during the day after drug administration in comparison toeither treatment alone.

Example 8

Each of the above examples is combined with bupropion 300 mg in onetablet formulated with MMX technology. Patients are observed for theappearance of secondary compulsive disorders and asked to answerquestions rating their hunger, satiety and well being after theadministration of the combination therapy. It is observed that thecombination therapy results in an improved score in hunger/satietysurvey conducted post dosing or reduced food intake measured during theday after drug administration in comparison to either treatment alone.

The following references are included in the application by reference intheir entirety.

-   1. Mayo Clin. Proc. 1993, Vol 68, 978 incorporated herein by    reference-   2. U.S. Pat. No. 7,431,943 B1 incorporated herein by reference-   3. Diabetes, Obesity and Metabolism, 9 (Suppl. 1), 2007, 23-31    incorporated herein by reference.-   4. Toft-Nielsen M B, Damholt M B, Madsbad S et al. Determinants of    the impaired secretion of glucagon-like peptide-1 in type 2 diabetic    patients. J Clin Endocrinol Metab 2001; 86:3717-3723.-   5. Rask E, Olsson T, Soderberg S et al. Impaired incretin response    after a mixed meal is associated with insulin resistance in    nondiabetic men. Diabetes Care 2001; 24:1640-1645.-   6. Provisional patent application for BIOK001 PR 61/143,951    incorporated herein by reference.

What is claimed is:
 1. A method of treating type II diabetes in anindividual consisting of: a) selecting glutamine formulated to releasein an oral colon targeted delivery system; b) orally administeringsufficient formulated glutamine to the individual via a colon targeteddelivery system sufficient to treat type II diabetes, wherein the amountof glutamine administered is in the range of 0.3 to 30 mg/kg body weightper day; and c) orally administering an amount of a monoamine reuptakeinhibitor to the individual sufficient to ameliorate an increase incompulsive behavior caused by step b.
 2. A method according to claim 1wherein the oral colon targeted delivery system is selected from thegroup consisting of a matrix within matrix delivery system, covalentlinkage compositions, polymer coated compositions, compositions embeddedin matrices, time released compositions, redox-sensitive compositions,bioadhesive compositions, micropartical coating compositions and osmoticdelivery compositions.
 3. A method according to claim 2 wherein thecolon targeted delivery system is a controlled release formulation of ahydrophilic first matrix, comprising a lipophilic phase and anamphiphilic phase wherein the lipophilic phase and the amphiphilic phaseare in a second matrix together and said second matrix is dispersedthroughout the hydrophilic first matrix wherein the lipophilic phase isat least partially incorporated into the amphiphilic phase.
 4. A methodaccording to claim 1 wherein the monoamine reuptake inhibitor isbuproprion.
 5. A method according to claim 1 wherein the glutaminestimulates the production of an L-cell secreted gut hormone.
 6. A methodaccording to claim 5 wherein the gut hormone from L-cells is selectedfrom the group consisting of GLP-1, GLP-2, PYY and oxyntomodulin.
 7. Amethod according to claim 6 wherein the gut hormone is GLP-1.
 8. Apharmaceutical composition for the treatment of type II diabetesconsisting of; a) an oral administered glutamine formulated in an oralcolon targeted delivery system such that it does not release in eitherthe stomach or upper gastrointestinal tract; and b) an oral administeredmonoamine reuptake inhibitor.
 9. A composition according to claim 8wherein the oral colon targeted delivery system is a matrix withinmatrix system, covalent linkage compositions, polymer coatedcompositions, compositions embedded in matrices, time releasedcompositions, redox-sensitive compositions, bioadhesive compositions,micropartical coating compositions and osmotic delivery compositions.10. A composition according to claim 8 wherein the monoamine reuptakeinhibitor is buproprion.